NM_007194.4(CHEK2):c.663C>G (p.Ile221Met) AND Familial cancer of breast

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Feb 6, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000204676.18

Allele description [Variation Report for NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)]

NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)

Gene:

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.1

Genomic location:

Preferred name:

NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)

Other names:

p.I221M:ATC>ATG

HGVS:

NC_000022.11:g.28719415G>C
NG_008150.2:g.27452C>G
NM_001005735.2:c.792C>G
NM_001257387.2:c.-1C>G
NM_001349956.2:c.482+5471C>G
NM_007194.4:c.663C>GMANE SELECT
NM_145862.2:c.663C>G
NP_001005735.1:p.Ile264Met
NP_009125.1:p.Ile221Met
NP_665861.1:p.Ile221Met
LRG_302t1:c.663C>G
LRG_302:g.27452C>G
LRG_302p1:p.Ile221Met
NC_000022.10:g.29115403G>C
NM_001257387.1:c.-1C>G
NM_007194.3:c.663C>G
p.I221M

Protein change:

I221M

Links:

dbSNP: rs200451612

NCBI 1000 Genomes Browser:

rs200451612

Molecular consequence:

NM_001257387.2:c.-1C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001349956.2:c.482+5471C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001005735.2:c.792C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.663C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.663C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: BREAST CANCER, FAMILIAL; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000261064	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21244692, 28492532
SCV000785252	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jun 13, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21244692, 27720647, 27153395 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004020215	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 9, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004215844	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.

Le Calvez-Kelm F, Lesueur F, Damiola F, Vallée M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB; Breast Cancer Family Registry, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV.

Breast Cancer Res. 2011 Jan 18;13(1):R6. doi: 10.1186/bcr2810.

PubMed [citation]

PMID:: 21244692
PMCID:: PMC3109572

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000261064.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 221 of the CHEK2 protein (p.Ile221Met). This variant is present in population databases (rs200451612, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 142342). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000785252.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004020215.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004215844.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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